Clot detection methods for clotting time testing

ABSTRACT

Aspects of the disclosure relate to clotting time tests detect clotting time based on the viscosity changes of a fluid sample, using a disk dropped within a test chamber containing the fluid sample from a disk maximal position to a disk minimal position, which is a point at which the disk settles within the fluid sample. Changes in the disk minimal position as multiple test cycles are conducted are used in assessing formation of a clot within the fluid sample. Methods of assessing such changes in the disk minimal position are disclosed.

TECHNICAL FIELD

The present disclosure relates to detecting changes in viscosity ofbiologic fluid test samples, e.g., detecting coagulation andcoagulation-related activities including agglutination and fibrinolysisof human blood test samples, and more particularly to improved methodsand apparatus for early detection of a clotting event in a blood testsample.

BACKGROUND

Blood coagulation is a complex chemical and physical reaction thatoccurs when blood comes into contact with an activating agent, such asan activating surface or other activating agent. In this context, theterm “blood” means whole blood, citrated blood, platelet concentrate,plasma, or control mixtures of plasma and blood cells, unless otherwisespecifically called out otherwise; the term particularly includesheparinized blood.

Several tests of coagulation are routinely utilized to assess thecomplicated cascade of events leading to blood clot formation and testfor the presence of abnormalities or inhibitors of this process. Amongthese tests are activated clotting time (ACT), which includes high rangeACT (HRACT), a test which features a slope response to moderate to highheparin levels (up to 6 U/mL) in whole blood drawn from a patient duringcardiac surgery. The ACT test formulated to respond to low heparinlevels (0.1 to 1.0 U/mL) in whole blood drawn from a patient during theextracorporeal membrane oxygenation (ECMO) procedure is low range ACT(LRACT).

Unfractionated heparin is most commonly used for anticoagulation duringcardiac pulmonary bypass (CPB) surgery to prevent gross clotting of thebypass circuit and more activation and consumption of coagulation systemcomponents. While an ACT test responds to heparin, it is a globalassessment of coagulation status of blood and affected by many otherfactors other than heparin, such as hemodilution and temperature. Due tothe limitation of ACT monitoring and the variability of patient responseto heparin dose, individualized heparin and protamine management basedon heparin protamine titration test has associated with improvedclinical outcomes. The heparin protamine titration test uses activatedclotting time as test end point.

During heart bypass surgery, the platelets of blood circulated in anextracorporeal circuit may become activated by contact with thematerials present in the extracorporeal circuit. This activation may bereversible or irreversible. Once platelets are irreversibly activated,they lose their ability to function further. A deficiency of functionalplatelets in the blood may be indicative of an increased probability ofa post-operative bleeding problem. Such a deficiency, and the resultingpost-operative bleeding risk, could be remedied by a transfusion ofplatelet concentrate. Platelet functionality tests, which can useactivated clotting time as a test end point, can identify a deficiencyof platelets or functional platelets and aid the attending surgeon inascertaining when to administer a platelet concentrate transfusion. Sucha test is further useful in ascertaining the efficacy of a platelettransfusion. By performing the platelet functionality test following aplatelet transfusion, it is possible to determine if additional plateletconcentrate transfusions are indicated. Real-time assessment of clottingfunction at the operative site may be performed to evaluate the resultof therapeutic interventions and also to test and optimize, a priori,the treatment choice and dosage.

Other anticoagulant drugs used in cardiac surgery and cardiaccatheterization procedures, such as low molecular weight heparin andbivalirudin, are also monitored with activated clotting time. Theclotting time test used to monitor bivalirudin uses ecarin as activator,thus the test is called ecarin time (ECT).

ACT tests are based on the viscosity change of a test sample within atest chamber. During a test cycle, a ferromagnetic washer immersed inthe test sample is lifted to the top of the test chamber by magneticforce produced by a magnetic field located at the top of the testchamber; the washer is then held at the top of the test chamber for aspecific time. After the specified holding time, the washer is thendropped through the test sample via gravity. The increased viscosity dueto the clotting of the test sample slows the motion of the washer. Thus,if the time that the washer travels through a specified distance (i.e.,the washer “drop time”) is greater than a preset value (the clotdetection sensitivity threshold), a clot is indicated to be detected andan ACT value is reported.

A particular apparatus and method for detecting changes in human bloodviscosity based on this principle is disclosed in U.S. Pat. Nos.5,629,209 and 6,613,286, in which heparinized blood is introduced into atest cartridge through an injection port and fills a bloodreceiving/dispensing reservoir. The blood then moves from the reservoirthrough at least one conduit into at least one blood-receiving chamberwhere it is subjected to a viscosity test. A freely movableferromagnetic washer is also located within the blood-receiving chamberthat is moved up using an electromagnet of the test apparatus andallowed to drop with the force of gravity. Changes in the viscosity ofthe blood that the ferromagnetic washer falls through are detected bydetermining the position of the ferromagnetic washer in theblood-receiving chamber in a given time, or by a given number of risesand falls of the ferromagnetic washer. Air in the conduit andblood-receiving chamber is vented to atmosphere through a further ventconduit and an air vent/fluid plug as the blood sample is fills theblood-receiving chamber.

The movement of the washer in the above approach is actively controlledonly when it is moved up, and the washer passively drops with the forceof gravity. Increased viscosity from blood clotting decreases thevelocity of the washer drops in the test chamber. A drop time greaterthan a preset threshold value indicates clotting of the test sample.Blood samples which have high levels of heparin usually produce veryweak clots that may easily be destroyed by the lifting movement of thewasher. If the clot threshold is set low to detect the weak clots,however, false detections often occur during early testing cycles whenactivators are not fully suspended during the mixing cycle.

The present disclosure addresses problems and limitations associatedwith the related art.

SUMMARY

Aspects of the present disclosure relate to methods for detecting ablood clot in a fluid sample at an early clot formation stage based on afluid viscosity change of the sample. Aspects of the disclosure can beused in clotting time tests to increase test sensitivity. Examples ofClotting Time tests in which aspects of the present disclosure areuseful include, but are not limited to, Activated Clotting Time (ACT),Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT), andEcarin Clotting Time (ECT).

The ACT test is one of the tests most widely used to monitor the effectof high level of heparin (up to 6 U/ml) in the sample during cardiacpulmonary bypass surgery. During a test cycle of the disclosed methods,a ferromagnetic disk is positioned at a Disk Maximum Position within atest chamber of a fluid viscosity testing device by magnetic forceproduced by the magnetic field. The disk is then held at the DiskMaximum Position for a specified time. After the specified holding time,the magnetic force is released so that the disk falls through the fluidsample due to the force of gravity to a Disk Minimum Position.Parameters relating to the disk movement indicative of a change in fluidviscosity can be measured with a position detector.

It is advantageous to detect clots in the fluid sample as quickly aspossible. Therefore, the threshold(s) in which changes in the fluidsample are compared to identify a clot are often set low. Low changethresholds, however, can potentially result false detection of clots(i.e. erroneous test results) due to noises of sensors, disk positions,and reagent uniformity, for example. Therefore, any clot detectionthresholds need to be at a value to avoid false detection. The presentinventors have discovered that by evaluating a change in the DiskMinimum Position (i.e. the lowest point within the test chamber in whichthe disk falls during a test cycle) and/or integration of a Disk MinimumPosition in a Disk Minimum Sum over a certain test period(s) asadditional or sole clot detection end point or threshold, clot formationcan be accurately detected at an early clot formation stage. It isbelieved that one advantage of evaluating changes in the Disk MinimalPosition is that an increase in Disk Minimal Position or integration ofDisk Minimal Position between test cycles is more reliably related toclot formation and less affected by potential noise introduced byposition sensors and disk movement as compared other disclosed clotdetection parameters assessed such as Disk Drop Span as a function oftest time or Disk Drop Velocity as a function of test time.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other advantages and features will be more readily understoodfrom the following detailed description of various embodiments, whenconsidered in conjunction with the drawings, in which like referencenumerals indicate identical structures throughout the several views, andin which:

FIG. 1, which is based on FIG. 13 of U.S. Pat. No. 5,629,209, is across-sectional view of a cartridge positioned within a machine.

FIG. 2, which is based on FIG. 12d of U.S. Pat. No. 5,629,209, is apartial cross-sectional view of the cartridge of FIG. 1.

FIG. 3 is a schematic cross-section of the test chamber portion of thecartridge of FIGS. 1 and 2.

FIG. 4A is a flowchart of a first embodiment, a portion of which isshown in greater detail in FIG. 4B

FIG. 5 is a flowchart of a second embodiment.

FIG. 6 is a schematic illustration of portions of the second embodiment.

FIG. 7 is a set of four graphs, one for each of four zones, showing zonecounts and scale factors as a function of time.

FIG. 8 is a set of four graphs, one for each of four zones, showinganother set of zone counts and scale factors as a function of time.

FIG. 9 is a schematic graph of the components of a Disk Cycle.

FIG. 10 is a schematic graph of the disk Distance Span over the DropPortion of a Disk Cycle.

FIG. 11 is a schematic graph of parameters related to the Disk DropVelocity.

FIG. 12 is a schematic graph of parameters related to the Disk Scale.

FIGS. 13 and 14 are schematic graphs of the Drop Velocity Calibrationprocess in first and second passes, respectively.

FIG. 15 is a flowchart of a third embodiment.

FIGS. 16-18 are sets of paired graphs (two graphs in each figure),showing measurements of various results of testing of the thirdembodiment.

FIG. 19 is a flowchart of a fourth embodiment.

FIG. 20 is a flowchart of a fifth embodiment.

FIG. 21 is a graph of a Disk Drop Distance (span) as a function of testtime for one example.

FIG. 22 is a graph of Disk Drop Velocity as a function of test time forthe example of FIG. 21.

FIG. 23 is a graph of Disk Minimal Position as a function of test timefor the example of FIGS. 21-22.

FIG. 24 is a graph of a Distance Minimum Sum as a function of test timefor the example of FIGS. 21-23.

DETAILED DESCRIPTION

In the following detailed description, references are made toillustrative embodiments of methods and apparatus for carrying out theclaims. It is understood that other embodiments can be utilized withoutdeparting from the scope of the claims. Illustrative methods andapparatus are described for performing blood coagulation tests of thetype described above. In the context of the present application, theterm “blood” means whole blood, citrated blood, platelet concentrate,plasma, or control mixtures of plasma and blood cells, unless otherwisespecifically called out otherwise; the term particularly includesheparinized blood.

FIG. 1 illustrates some basic features of a possible apparatus orsystem, components of which are further described in U.S. Pat. No.5,629,209, the entirety of which is incorporated by reference. Acartridge 100, having been inserted into a side 16 of a machine 10, issecured within a cartridge holder 302. An aperture 28 enables a fluidsample to be introduced into the cartridge 100 after the cartridge 100is inserted into the machine 10. An air vent/fluid plug device 120 isaligned over a hole 304 in the base of the cartridge holder 302 topermit escape of air that is vented from the cartridge 100 during themovement of the fluid sample into its respective fluid-receivingchamber. Each fluid-receiving chamber is typically associated with anapparatus for moving a ferromagnetic material (hereinafter “disk”, e.g.,a washer or the like made of a ferromagnetic material) provided by themachine 10, such as an electromagnet 122, and a position detector fordetecting the position of the disk 116 within a test chamber 114, e.g.,a detector 124. The term “disk” as used herein is intended to includeany object of a multitude of configurations at least partially comprisedof ferromagnetic material such that the disk can move within the testchamber and be lifted with the electromagnet 122. A radio frequencydetector, for example, may be conveniently employed for the detector124. It should be noted that the detector 124 is not limited to thedetection of ferromagnetic material but is capable of detecting anymetallic substance placed within the test chamber 114. The electromagnet122 and the position detector 124 are connected to a circuit board 300and thereby operatively connected to an associated computer processor(not shown) which receives information, provides directions, andcalculates intermediate or final values relevant to the tests. Theprocessor is under control of programming executed by the processor asrequired. For simplicity of illustration, only one fluid-receiving testchamber 114, electromagnet 122, and position detector 124 are shown. Thecartridge 100 may have a plurality of such arrangements for alternativeand/or comparative tests.

FIG. 2 illustrates that fluid sample 200 fills the fluid-receivingchamber and reaches the air vent/fluid plug device 120 to establish afluid lock. The ferromagnetic disk 116 is moved between a restingposition on the bottom of the fluid-receiving chamber 114 and the top ofthe chamber 114 as the electromagnet 122 is energized; if theelectromagnet 122 is turned off, the disk 116, under the force ofgravity, falls at least partially through the fluid sample 200 towardthe bottom of the chamber 114. The position detector 124 measures one ormore parameters (e.g., the time required for the disk 116 to fall fromthe top to the bottom of the chamber 114) and sends this information tothe associated computer. As the viscosity of the fluid sample 200increases, the measured time increases. Indeed, in the case of bloodcoagulation, eventually, the disk 116 is unable to move through a bloodsample to the bottom of the test chamber 114.

When the fluid sample 200 whose viscosity is being measured is blood,the motion of the disk 116 through the blood also has the effect ofactivating the clotting process of the blood. The activation effect canbe enhanced when the surface of the disk 116 is optionally roughened inknown ways, as such techniques increase the surface area of the disk. Ifeven faster clotting times are desired, a viscosity-altering substancemay be used. For example, a clotting activator such as tissue factorthromboplastin can be added to the cartridge, or a particulate activatorsuch as diatomaceous earth or kaolin may be used either alone or incombination with other activators such as phospholipids or tissuefactors.

The position detector 124 in one embodiment is a radio frequencydetector. Radio frequency detectors sense the position of the disk 116by sensing the changes in the magnetic field surrounding the detectioncoil of the radio frequency detector that are caused by the presence ofthe disk 116. Radio frequency detectors have sensitivity toferromagnetic and other metallic materials and resistance to effectscaused by other elements of the device, such as the fluid. It should beunderstood, however, that other types of position detectors 124 arecontemplated. For example, in another embodiment, the position detector124 is a Hall effect sensor and its associated circuitry, as generallydescribed in U.S. Pat. No. 7,775,976 (the entirety of which isincorporated by reference) at column 16, line 15 to column 17, line 5.

In a typical sequence, the test cartridge 100 is inserted into the side16 of the machine 10 through the slot 26, and the disk 116 is lifted anddropped a number (e.g., three) times by electromagnet 122. This providesthe average values for the minimum and maximum positions and distancesthat disk 116 travels without fluid sample 200. This process also servesas a system self-test to verify the functions of cartridge 100 andmachine 10.

After the initial testing, a sample mix cycle begins the test protocol.The test cartridge 100 is filled with the fluid sample 200 and then theelectromagnet 122 initially raises and lowers the disk 116 rapidlyseveral times to further mix the fluid sample 200 with anyviscosity-altering substance present and, if the fluid sample 200 isblood, promote activation of clotting, as discussed above. The fluidsample 200 is then allowed to rest for a short time, the duration ofwhich depends on test type. For example, in a heparin protaminetitration test, the test cycle may be initiated immediately after thesample mix cycles.

During the subsequent coagulation test phase itself, the electromagnet122 raises the disk 116 repeatedly at a slower rate and/or reducedlifting power. After each elevation of the disk, the position detector124 is used to determine the “fall time” (or “drop time”), i.e., thetime taken for the disk 116 to fall to the bottom of the chamber 114.Absence of an increase in fall time suggests a lack of coagulation andthe test continues. But an increase in fall time suggests a change inviscosity, measured in terms of the amount of fall time as compared to abaseline value. All data, including individual test results, may bedisplayed, stored in memory, printed, or sent to another computer, orany combination of the same. It is envisioned that the fluid viscositytesting device used with the embodiments disclosed herein can be thatdescribed above or can be a different fluid viscosity testing devicethat operates in a similar manner.

The geometry which underlies one possible initial clot detectionalgorithm is schematically illustrated in FIG. 3. The electromagnet 122,position detector 124, and fluid 200 have been omitted for clarity only.Similarly, the height of the chamber 114 is exaggerated relative to thethickness of the disk 116 only for purposes of illustration. The firstembodiment of a clot detection algorithm which relies on this geometryis illustrated in the flowchart of FIGS. 4A-4B.

The clot detection algorithm 400 of FIG. 4A considers the total diskdrop distance to be represented by a plurality of zones, such as fourzones. The zones are not necessarily equally sized. In the embodimentillustrated, the four zones are (from top to bottom) labeled Zone 0, 1,2 and 3. Because the total disk drop distance is determined by thegeometry of the apparatus, it is determined at 410 in the following way:(1) the minimal and maximum positions of the disk are measured by thethree initial lift and drop cycles before introduction of fluid 200; (2)the average values of the minimum (min) and maximum (max) are computed,and the initial disk travel distance is then calculated by the productof a factor and the difference between the maximum and minimum. Thefactor may be a hard-coded value slightly less than 1.0 (such as 0.91),so that the slight amount of time required for the disk to be releasedfrom the magnet is not included in the drop time; (3) the time of thedisk dropping through the initial range [(0.91)×(max−min)] is measuredand divided by 4 to yield a drop time for each of the four zones; (4)the end of zone positions are found by capturing the position values foreach zone. The sample mix cycle is not required by the clot detectionalgorithm and therefore is not shown in FIG. 4A.

This embodiment thus relies on a calculation of disk velocity as thedependent variable, a value of distance as a constant, and time as theindependent variable. As will be seen below, in an alternativeembodiment, the roles of distance and time will be reversed.

The algorithm continues at 420 by determining the disk drop times (or,“zone counts”) of an initial number of disk drops after the sample mixcycle described above. These values are summed together for each zone inthe plurality of zones. A possible value for the initial number of diskdrops is four.

Next, a sensitivity scale factor (1-100%) is invoked; this value isdetermined separately from the disk drop times and thus it may behard-coded into the algorithm or preset in a parameter data file. Thevalue of the sensitivity scale factor may vary over the course of theactual test cycles (discussed further below), but in this firstembodiment the sensitivity scale factor is a constant.

Once the sensitivity scale factor is invoked, the clot detectionthreshold for each zone is calculated at 430 as the sum of the washerdrop times of the initial number of drops, multiplied by the sensitivityscale factor.

The actual clot detection process then begins at 440. During thecoagulation test phase, the disk is repeatedly lifted and dropped as inthe conventional process described earlier. The disk drop times arecounted on a per-zone basis for each of the plurality of zones that makeup the total disk drop distance, as opposed to a single measurementbased on the entire distance.

The clot detection algorithm may use the outcome of any one of aplurality of criteria applied at 450 to detect a clot. A possible numberof criteria is five. Any criterion may or may not depend upon thesensitivity scale factor described above. Examples of criteria which donot depend upon the sensitivity scale include three criteria whichidentify non-movement of the disk: (a) at 451, the disk does not dropfrom the top, i.e., it remains in zone 0; (b) at 455, the disk does notrise from the bottom, i.e., it remains in zone 3; and (c) at 453, thedisk moves too slowly through any zone, i.e., it is moving but does notleave any of zones 0-3 in less time than a threshold value. For example,in a system such that the disk in the absence of clots would have a droptime over the entire distance on the order of 200 msec or less, thatvalue is a suitable threshold for any one zone; if the disk spends asmuch time in a single zone as it would be expected to spend over thedistance represented by all zones in the absence of clotting, it can beassumed that the disk is not moving due to the increased viscosity ofthe clotted sample.

Other criteria rely on the clot detection threshold that is derived fromthe sensitivity scale factor. Specifically, one criterion is that thezone counts of each of a pair of zones are greater than their respectiveclot detection thresholds. In another embodiment, more than one suchpair of zones is established, i.e., two separate criteria of this typeare considered. Such criteria may be: (d) at 453, the zone counts ofzone 1 and zone 3 are each greater than their respective thresholds; and(e) at 454, the zone counts of zone 2 and zone 3 are each greater thantheir respective thresholds. Other combinations of zones may be selectedin other embodiments. While either such criterion could be used as the(only) fourth criteria in addition to the three criteria above, theyboth may be used as the fourth and fifth independent criteria fordetecting clot formation.

As noted before, taking all of the five criteria (a)-(e) together, anyone such criterion may be used to consider a clot detected, but all fivemay be considered at once and any one of the five alone may be used todetermine clot detection.

A second embodiment 500 is generally illustrated in the flowchart ofFIG. 5. The second embodiment addresses a possible problem presented byusing a constant sensitivity scale factor. If the constant value of thesensitivity scale factor is too low, false detection is possible,particularly during the initial test cycles when disk movements are notyet stabilized. This is because dry kaolin that is not fully mixed anddispersed during the initial mix cycle interferes with accurateassessment of the disk drop rates early in the test phase. However, ifthe value is too large, weak clots (i.e., clots which do not producesignificant change in viscosity) may not be detected at all,particularly later in the test phase when the amount of unmixed drykaolin is reduced by subsequent agitation during prior portions of thetest phase.

To address this, the sensitivity scale factor (1-100%) may take ondifferent values during different portions of the coagulation test phasein this second embodiment, as opposed to the first embodiment above, inwhich the sensitivity scale is a constant throughout the test phase.

In an approach to this second embodiment, as illustrated schematicallyin FIG. 6, the coagulation test phase is divided into smaller periods;as illustrated, the entire coagulation test phase is divided into threetest periods which are labeled 1, 2 and 3. The duration of eachcoagulation test period is either hard-coded into the algorithm or is avalue obtained from a parameter file at 510.

At 530, the clot detection threshold or end point is determined for eachof the three periods. During the initial period, Test Period 1, whichmay be on the order of 0 seconds to a value in the range of 30 to 100seconds, the clot detection sensitivity scale factor, F₀, may beobtained from a parameter file. A transition period, Test Period 2,begins at the end of Test Period 1 and may extend to a value on theorder of 400 to 500 seconds in total elapsed time. During Test Period 2,the sensitivity scale is reduced from the initial value of F₀. The rateof reduction may be obtained from a parameter file. In general, the rateof reduction could be a constant value or a function of time or otherparameters, such as an exponential decay. An exponential decay providesfor a smoother transition. The final period, Test Period 3, begins atthe end of Test Period 2 (if present, as illustrated) and extends to theconclusion of the test, typically 999 or 1,000 seconds. During TestPeriod 3, the sensitivity scale is constant at the reduced value F₁which results from the steady reduction of the threshold value from F₀.

Thus, over the course of the three test periods, the sensitivity scalefactor is relatively high during the first test period, which istypically when compounds (e.g., kaolin) are mixing with the blood andthe washer location has not yet stabilized. The relatively high valueavoids false detection of clots during such mixing. The loweredsensitivity in the third test period allows detection of weak clots. Inthe broadest implementation, only the initial and final (first andthird) test periods are required; all that is required are relativelyhigh and low values of the sensitivity scale factor. However, the secondtransition test period after the initial and before the subsequent finalperiod will ensure a smooth transition between the two values. Althoughnot illustrated here, additional periods (fourth, fifth, etc.) and scalefactors values are possible but not required by this embodiment of theclot detection algorithm.

After the threshold value is determined for the current test period, theclot detection algorithm 450 is employed as described above.

Example 1

FIG. 6 shows an example of disk drop time monitored during a NG-HMSHR-ACT test as generally described above. This example shows how a clotis detected via the modified clot detection algorithm. In this example,a clot is detected by comparing disk drop times measured in Zones 1, 2and 3 against the clot detection thresholds of their respective zones.

The pertinent data and parameters are summarized below in Table 1.Initial threshold values were established at 30 seconds after thebeginning of the test phase and final threshold values were establishedat 400 seconds (i.e., the transition period was 370 seconds induration). The reduction in the threshold values was exponential at therate indicated.

TABLE 1 Sum of Percentage Final Zone Four Initial Initial Final FinalReduction Count at Time Initial Four Values Zones Scale Threshold ScaleThreshold in Threshold of Clot Zone (msec) (msec) Factor (msec) Factor(msec) from Initial Detection 0 24 24 24 24 96 75% 72 0.4884 46 45% 65 140 40 40 40 160 75% 120 0.4884 78 43% 82 2 45 45 45 45 180 75% 1350.4884 87 44% 68 3 35 35 35 35 140 75% 105 0.4884 68 43% 83

The data in the above table shows the drop times for the initial fourdrops in the each of the four zones. The drop times are scaled to theinitial sensitivity scale factor to produce the initial threshold. Asthe scale factor is attenuated down, the threshold decreases for eachzone (by 27% in this example). At the time of clot detection, the zonecounts for Zone 1 and Zone 3 exceed their respective thresholds, andthus the criterion 453 (see FIG. 4B) has been met. Therefore, clotdetection (end point) is triggered.

The data in this example shows that the disk drop times in each of thefour zones generally decreased over the initial 400 seconds, thenincreased afterward. This is consistent with the dispersion of drykaolin during the early portion of the test period. Kaolin reagent isnot fully dispersed during the mixing period and therefore initiallyproduces a longer drop time. When the kaolin is fully dispersed, thedrop time decreases. After clot formation, the drop time increases (thisis also illustrated in the data of FIG. 8). This illustrates why theindividual zone threshold value needs to set high in the early portionof the test period, so that the change in washer drop time caused by drykaolin dispersion will not generate false clot detection. After the 400second mark, as the threshold values are held constant at theirrespective reduced values, the increased washer drop times exceed thezone threshold values in Zones 0, 1, and 3 after a cumulative time ofapproximately 750 seconds. The criteria for clot formation are metbecause the threshold values in both Zones 1 and 3 are exceeded. Infact, for this specific data, in every case, the zone counts 700exceeded the clot detection thresholds 710 during Test Period 3. Thisprovides further support that alternative clot detection criteria couldbe formed from combinations of conditions other than those listed above.

A third embodiment is best explained with the following comprehensivedescription which repeats some of the description of the first twoembodiments. However, this is solely for convenience and should not beunderstood to limit the scope of any embodiments of the invention in anymanner. Thus, as before, the instrument or machine 10 is designed tomeasure the clotting capability of a patient's blood. The measurement isexpressed as the amount of time it takes for a freshly drawn sample ofblood to clot. The instrument operates using a disposable cartridge 100that can hold a small amount of blood. The instrument keeps thecartridge 100 and blood sample 200 at a temperature equivalent to normalhuman body temperature. The cartridge 100 contains chemicals thataccelerate the clotting of blood 200 in a known manner, so a clottingtest can be completed quickly. The blood is injected at a syringefitting on the cartridge, and fills a number of separate channels in thecartridge. In each channel, there is a well containing a metal disk orwasher 116. The disk 116 is free to move up and down within the well114. For each channel, the instrument has an electromagnet 122positioned above the well that can be activated to lift the disk, ordeactivated to drop the disk 116. There is also an inductive sensor 124positioned below the well that can measure the vertical position of thedisk in the well, and a capacitive sensor that detects when the well isfull of blood.

To run a test of a blood sample's clotting capability, an operator willinsert a fresh, unused cartridge 100 in the instrument and inject theblood 200. The instrument 10 then repeatedly accesses the electromagnets122 to lift and drop each disk 116, while monitoring the disk positionsensors 124 to evaluate the resulting movement of the disk. When theblood is first injected, each disk should be seen to freely move up anddown in the well. As a test progresses and clots start to form in theblood, the movement of each disk should be seen to slow or stop due tointerference from the clots. When the blood clots, the instrumentoutputs the elapsed test time that was required to achieve the clot.This is the desired measure of the blood sample's clotting capability.

There may be a number of different cartridge types used with theinstrument. If so, typically each type has a specific mixture ofchemicals designed for a specific type of clotting test. Some cartridgetypes use all channels, while others use only some of the channels. Tosupport different cartridge types (if present), the instrument may bemulti-functional, i.e., the operational methods (or “algorithm”)performed by the computer processor connected to circuit board 300 maybe parameterized. For example, numerous aspects of disk control andmeasurement are driven by configurable parameters. For each cartridgetype, there is a unique set of predefined constants used to initializethe parameters when that cartridge is used. Key parameters that drive atest may present tradeoffs in setting the parameters for a specific typeof cartridge. The system may have a separate copy of the cartridgeconfiguration parameter settings for each defined cartridge type. Thecartridge type may be indicated by a cartridge code number. Theinstrument may read or otherwise detect the number (e.g., by reading abar code or similar indicia, or by other techniques) from the cartridgeafter it is inserted into the system.

As noted above, operation of the instrument involves both control of adisk (lift and drop), and measurement of the resulting disk behavior(e.g., span of distance traveled and velocity of drop). As before,fundamental terms for disk control and measurement may be defined.

Referring in addition to FIG. 9, a disk or test cycle is a time periodover which a disk is lifted by the electromagnet, held at a disk maximumposition for a while, and then dropped and allowed to settle at the DiskMinimum Position. In many instances, the Disk Maximum Position may beproximate the top of the well. The lift portion of the cycle is theperiod of time from the beginning of the cycle until the disk isdropped. At the beginning of the lift, the electromagnet is activatedwith enough power to pull the disk up from within the well. Then thepower is reduced to a minimal level to hold the disk at the disk maximumposition. The power is reduced to zero to drop the disk.

Referring also to FIG. 10, during a disk cycle, the position sensor isaccessed to determine values relating to the span of travel of the disk,such as Disk Maximum Position/Distance Maximum (the vertical distance ofthe disk just before it is dropped), Disk Minimum Position/DistanceMinimum (the vertical distance of the disk after it is dropped andsettles), and Disk Drop Distance or disk Distance Span (the differencebetween Distance Maximum and Distance Minimum). Over the course of atest, a decrease in the disk Distance Span is an indication that clotsare forming and interfering with the span of travel of the disk throughthe fluid sample.

Turning to FIG. 11, also during a disk cycle, the position sensor isaccessed to determine values relating to the velocity of the disk duringthe drop, including Disk Drop Velocity (vertical distance dropped over afixed Drop Measurement Time elapsed after the disk drops below a TopSeparation Threshold). Since this value is computed as a distancetraveled per unit of time, it can be called a velocity measure. The TopSeparation Threshold and Fixed Drop Measurement Time are set toappropriate values during a Clot Test Calibrate operation as describedfurther below.

As defined here, the Disk Drop Velocity is only a rough measure of thespeed at which the disk dropped, but can be a reliable indicator of whenthe drop is being slowed by increasing viscosity of the blood sample dueto clotting. An instantaneous measure of the disk speed is considered tobe a less valuable indicator of clots, because it can vary widely amongdrops (even in the same sample at the same relative point in the diskcycle), due to variation in the way the disk drops (e.g., variation inthe amount of time it takes to separate from the electromagnet, and/orvariation in the angular orientation of the disk during the drop). Thesevariations have a large effect on instantaneous speed measurements, butonly minimal effect on the rough measure of speed. The velocity of thedisk is of interest only during the drop portion of the cycle. During adrop, the force on the disk is its weight due to gravity, which isconsistent from drop to drop. Thus, changes in the Disk Drop Velocity(disk velocity) from drop to drop are directly due to changes inviscosity of the blood. During a lift, the force on the disk varieswidely due to variations in its distance from the electromagnet,electromagnet power, angular orientation of the disk, etc. Thus, changesin disk velocity from lift to lift are not always due to viscositychanges alone. For this reason, it is possible to forego measurements ofthe disk velocity during the lift. Use of the Disk Drop Velocity measurealso provides more information about the state of the blood sample thanthe disk Distance Span measure alone. The disk may continue to have thefull span of travel from the top of the well to the bottom, but may slowsignificantly on the drops to the bottom. For some clot test types, theuse of Disk Drop Velocity is critical to declaring the sample clotted atthe correct elapsed test time.

Turning to FIG. 12, the Disk Scale is a set of scaling values relatingto control of the disk during the lift. They determine how hard theelectromagnet pulls on a disk during the lift portion of a cycle. TheDisk Scale consists of the following values: Estimated Distance Span(the estimated distance span of the well), Distance At Lift Start (thedistance value at the well bottom), Hold Power (the setpoint of theelectromagnet power level after the high power lift is complete), andLift Power Ticks Max (the maximum number of milliseconds in whichelectromagnet power can be set higher than the Hold Power at thebeginning of the lift portion of a cycle). Several other remainingvalues allow for setting the electromagnet power higher than the HoldPower when the vertical distance of the disk is at a value lower thanthe top of the well. They include Lift Zone 0 Distance Span Max (span ofdistance from the well bottom comprising lift zone 0), Lift Zone 0 Power(setpoint of electromagnet power level when the disk is in lift zone 0),Lift Zone 1 Distance Span Max (span of distance from the well bottomcomprising lift zone 1), Lift Zone 1 Power (setpoint of electromagnetpower level when the disk is in lift zone 1, and not in zone 0), LiftZone 2 Distance Span Max (span of distance from the well bottomcomprising lift zone 2), and Lift Zone 2 Power (electromagnet powerlevel to set when the disk is in lift zone 2, and not in zones 0 or 1).Other similar values can be established when there is a different numberof zones.

The lift zone power levels are meant to be applied for only a briefperiod of time (for example, approximately 10 msec) to pull the disk tothe top of the well. Once the disk is higher than the Lift Zone 2Distance Span Max, the electromagnet power level is set to a Hold Powervalue. If the disk never gets higher than Lift Zone 2 Distance Span Max,the power is switched to Hold Power after the time period defined byLift Power Ticks Max. Power levels higher than Hold Power are onlyallowed to be set for one cartridge channel at a time. The instrumentsequences the channels one at a time to perform the disk lifts. Therestrictions on electromagnet power ensure that the magnets do notgenerate heat in an amount sufficient to interfere with control of theblood sample temperature. The instrument may use a heater control loopto keep the blood sample at normal human body temperature.

Different settings of Disk Scale are used during the different phases ofoperation of a test (Cartridge Test, Mix, and Clot Test). The settingsare changed to suit the purposes of the test phase. For example, duringthe mix phase, high power levels are used during the lift to agitate theblood for mixing with the dry chemicals in the cartridge. During theclot test phase, lower power levels are used so that lifting of thedisks will not interfere with clot formation.

The instrument goes through three phases of operation to perform a testof a blood sample's clotting ability: Cartridge Test, Mix, and ClotTest.

When a cartridge is inserted into the instrument, the instrumentperforms a Cartridge Test to verify the disks all have a sufficient spanof travel. The Cartridge Test consists of a series of steps. First, theDisk Scale is set to values appropriate for lifting the disks inside anempty cartridge (fluid sample not yet added). The Estimated DistanceSpan value for each disk is set to a defined constant value, becausethere is no previous cycle data for this cartridge to give a betterestimate. Next, a series (e.g., three) of Disk Cycles is performed. Foreach Disk Cycle, the following data are gathered and saved for each diskdrop: Distance Minimum Position, Distance Maximum Position, and DistanceSpan. To pass the Cartridge Test, the data for each disk drop mustconform to the following criteria: (1) each Distance Span must begreater than a defined minimum value; and (2) the maximum variationbetween any Distance Span and the largest Distance Span must be lessthan a defined maximum value. If the Cartridge Test passes, the averageof the Distance Span values for each disk is saved, to be used as theEstimated Distance Span for the later test phases.

After the Cartridge Test, the instrument waits for the cartridge to befilled with blood by the operator. The fill sensors are polled untilthey indicate all channels are filled. When all channels are filled, theinstrument begins the Mix phase of the test.

The purpose of the Mix phase is to agitate the blood in order to mix itwith the dry chemicals contained in the cartridge wells. The Mix phaseconsists of the following steps. First, the Disk Scale is set to valuesappropriate for aggressively lifting the disks inside a blood-filledcartridge, and the Estimated Distance Span value for each disk is set tothe average of the Distance Span values measured during the CartridgeTest. Next, Disk Cycles are performed for the time duration allocatedfor the Mix phase. The Elapsed Test Time begins counting at thebeginning of the Mix phase. Later, when clotting is detected, theclotting time will be reported as the time since the beginning of theMix phase.

In the Clot Test phase, the disks are lifted and dropped for the solepurpose of detecting when clots have formed in the blood. The Clot Testconsists of the following steps. First, the Disk Scale is set to valuesappropriate for gently lifting the disks inside a blood-filledcartridge, and the Estimated Distance Span value for each disk is set tothe average of the Distance Span values measured during the CartridgeTest. Next, Disk Cycles are performed for the time duration allocated tothe Clot Test phase. For each cycle, various disk measurement data foreach disk are temporarily saved. These include distance data for each 1msec time increment of the first 500 msec of the drop portion of thecycle, if applicable. At the end of each cycle, the disk measurementdata can be used for a variety of purposes including a Clot TestCalibrate (in which the data is used for computing calibration valuesrepresenting Distance Span and Drop Velocity of the blood sample in anormal unclotted state) and Clot Test Evaluate (in which the data isused for computing Distance Span and Drop Velocity for comparisonagainst the calibration values, to determine if the blood sample hasreached a clotted state). (Further details of Clot Test Calibrate andClot Test Evaluate are discussed below.) The calibration data consistsof three cycles worth of disk measurement values.

The decision about whether to use the disk measurement data for ClotTest Calibrate or Clot Test Evaluate is made as follows. If this is oneof the first three cycles, then use the data for Clot Test Calibrate;but if this is not one of the first three cycles, but the currentDistance Span is greater than the smallest Distance Span in the savedcycles of calibration data, then replace that cycle of Distance Spandata with the current Distance Span for Clot Test Calibrate. This isnecessary because the Distance Span can increase over the initial cyclesof the Clot Test phase, as the dry chemicals continue to dissolve andallow for a greater span of travel of the disk. The calibration DistanceSpan must be recomputed to prepare for any clotting that occurs afterthis point. The calibration Drop Velocity is not changed from the valuecomputed over the first three cycles. When replacing a Distance Span andredoing Clot Test Calibrate for the span, it is possible to follow thatreplacement with a Clot Test Evaluate. Since the new Distance Span islarger than the calibration value it replaced, it is unlikely that aclot will be detected due to a change in Distance Span, but a clot couldbe detected due to a change in Drop Velocity. If neither of the abovetwo criteria are met, then the data is used for Clot Test Evaluate.

The purpose of the Clot Test Calibrate operation is to computecalibration values of Distance Span and Drop Velocity that representnormal values for the blood sample in an unclotted state. These valuesare best not computed until there are at least several (e.g., three)cycles of Clot Test drop data to analyze. In the case of three cycles,the calibration value for Distance Span is computed from the threeavailable cycles of distance span data by taking the Distance Spancalibration value as equal to the Largest Distance Maximum over thethree cycles less the Smallest Distance Minimum over the three cycles.When a different number of cycles is used, an analogous calculation maybe made. The calibration value for Distance Span is recomputed at everycycle where the new value of Distance Span is larger than one of thethree values used for the previous computation of the calibrationDistance Span. This is necessary because the Distance Span tends toincrease during the early part of the Clot Test phase, as the chemicalsin the cartridge well become fully dissolved. The calibration value forDrop Velocity is computed by analyzing the first three cycles of ClotTest drop data. The calibration value for Drop Velocity is computed onlyonce for each disk. It is not changed when the calibration value forDistance Span is recalculated on a later cycle due to an increase inspan.

Referring now to FIGS. 13 and 14, the Drop Velocity is a rough measureof the speed at which the disk drops from top to bottom of the well. Tocompute the calibration value, the drop data is analyzed in multiple(e.g., two) passes. This allows the Drop Velocity measurement to bescaled to the characteristics of the specific cartridge well and fluidsample being used; the way that a disk drops can be quite different inone sample containing a whole blood fluid versus another containing onlyblood plasma. In the first pass, the (three) cycles of disk dropmeasurement data are examined to determine the Measured Drop Time forthe disk to fall from top to bottom. To isolate this measurement fromthe normal signal noise of the position data, only a portion of the dropis considered. The Measured Drop Time is computed as a time that elapsesafter the disk falls below a Top Separation Threshold and before itenters a Bottom Separation Threshold. The Top Separation Threshold andBottom Separation Threshold are computed from cartridge configurationparameters that define them as a percentage of the Distance Span. (Notethat, while this implicitly creates three regions in the well, theseshould not be confused with the Zones established in the alternativeembodiment discussed above.) The average of the Measured Drop Timevalues over the (three) cycles is used as the Fixed Drop MeasurementTime for the second pass.

In the second pass, a Drop Velocity value is computed for each of the(three) cycles of drop data. Each Drop Velocity is computed as thevertical distance dropped over a Fixed Drop Measurement Time elapsedafter the disk drops below a Top Separation Threshold. The calibrationvalue of Drop Velocity is then set to a representative value, such asthe largest of the Drop Velocity values computed over the (three) cyclesof drop data. (In other variations, the representative value could bethe average or mean of the values.) The Fixed Drop Measurement Time andTop Separation Threshold are saved for computing Drop Velocity values inClot Test Evaluate operations throughout the remainder of the Clot Test.

It bears repeating that this embodiment, in contrast to the “Zoned”embodiment discussed above, relies on a calculation of disk velocity asthe dependent variable, taking distance as the independent variable andtime (specifically the Fixed Drop Measurement Time value) as a constant.

In order to pass the Clot Test Calibrate, the data for each disk mustconform to the following: each Distance Span must be greater than adefined minimum value, the maximum variation between any Distance Spanand the largest Distance Span must be less than a defined maximum value,each Drop Velocity must be greater than a defined minimum value, and themaximum variation between any Drop Velocity and the largest DropVelocity must be less than a defined maximum value. If the Clot TestCalibrate fails, then the channel will be indicated as already beingclotted. Otherwise the channel will continue to be processed in the ClotTest phase.

The purpose of the Clot Test Evaluate operation is to compare thecurrent values of one or both of Distance Span and Drop Velocity totheir respective calibration values, to determine if the channel isclotted. The exact criteria used when comparing the current values tothe calibration values are specific to each cartridge type, and aretherefore defined in the Cartridge Configuration Parameters when thatapproach is employed. Specifically, the Cartridge ConfigurationParameters define which one of the following sets of changes must occurin order for a channel to be declared clotted: (1) if Distance Spandrops below a threshold value, defined as a percentage of thecalibration Distance Span; (2) if Drop Velocity drops below a thresholdvalue, defined as a percentage of the calibration Drop Velocity; (3) ifeither Distance Span or Drop Velocity drops below its respectivethreshold value, i.e., either (1) or (2); and (4) if both Distance Spanand Drop Velocity drop below their threshold values, i.e., both (1) and(2). Once a channel is declared clotted, its elapsed clotting time iscaptured and the channel no longer undergoes Disk Cycles in the ClotTest phase.

For either Distance Span or Drop Velocity, one variation is to requirethat the clot detection threshold be reached for a number of consecutivecycles before a clot is declared. In that case, a further option is touse a specific one of those cycles as the cycle representing the elapsedclotting time. With this feature, a single low measurement of DistanceSpan or Drop Velocity might not result in a reported clot, but if thatmeasurement persists for a number of consecutive iterations, then thefirst occurrence of the measurement could be indicated as the clottingtime or end point. This is a way to guard against an anomalous eventthat might affect the measurement of a single cycle.

Other aspects of the first and second embodiments discussed above arealso applicable to this third embodiment. For example, over the courseof the test it is possible to do any or all of: change (especially, toincrease) the cycle times, change lift power levels, and change clotdetection thresholds, for the same reasons as noted above and using thesame or equivalent techniques. For example, the clot detectionsensitivity scale factor, or any other parameter relevant to at leastone of the plurality of criteria used to determine clot formation, maybe changed in a manner analogous to that illustrated in FIG. 6. Thisincludes optional variations such as holding the parameter equal to afirst constant value during an initial period of the plurality ofperiods, and at a second constant value (lower than the first constantvalue), during a subsequent third period of the plurality of periods;the initial period and the subsequent period may be separated by atransition period during which the parameter is reduced from the firstconstant value to the second constant value. The parameter may bereduced during the transition period at a constant rate, orexponentially, during the transition period.

FIG. 15 is a summary 600 of this third embodiment as described in detailabove, in a flowchart form analogous to that of FIG. 5 for the secondembodiment. At 610, the disk drop distance is found and divided intolift zones. At 620, the disk drop time is found and thus the disk dropvelocity is computed. Separately, at 625, the test cycles are dividedinto test periods. These two inputs enter step 630, in which the diskdrop distance and velocity values are updated if appropriate, and theninto 640 in which the disk drop distance and/or velocity are compared totheir respective threshold values. Based on such comparison(s), thedecision 650 is made whether to consider the clot detected or tocontinue the testing (updating values as noted before).

FIGS. 16-17 illustrate the importance of considering either or both ofdisk travel distance (span) and velocity, depending on the assay andidentity of sample fluid being tested. Each figure is a pair of graphscomparing results of test measurements related to the third embodiment.FIG. 16 illustrates measurements of disk travel distance (span) on theleft and disk velocity on the right, both measured in plasma from acommon sample and in the same channel of a test apparatus. As can beseen, the steep and sudden decrease span and velocity afterapproximately forty-five seconds demonstrates that either parametercould be used to detect a clot, and further that the combination of thetwo parameters could be also be used. By contrast, FIG. 17 is a similarillustration of those two parameters in samples of fresh whole blood(“FWB”), again in a common channel. A comparison of the two graphs showsthat even if span length remains essentially unchanged (left graph), asudden decrease in disk velocity (right graph) may be used alone tosignal clot formation.

FIG. 18 compares the drop delay time (i.e., the time in the topseparation zone) between samples of FWB (on the left) and plasma (on theright) in different channels. It illustrates that the former isrelatively insensitive to change with time, even times as long as nearly150 seconds; whereas the latter exhibits a sudden and dramatic increasefrom a very stable value (approximately 30 msec on average) afterapproximately 50 seconds of test duration. The results show that thedisk drop delay time is dependent on viscosity because the values aresignificantly greater for FWB than for plasma. The average fixed dropmeasurement time in the unclotted plasma in this example was 40 msec andfor the unclotted FWB it was 107 msec.

Referring now also to a fourth embodiment 700, which is summarized inFIG. 19 and utilizes many processes, principles and equipment discussedabove. At step 710, the test cycles are optionally divided into aplurality of test periods (e.g., two, three or more). At step 712, aDisk Drop Distance (disk Distance Span) is determined and the diskDistance Span is optionally divided in a plurality of zones (e.g.,three) as described above with respect to prior embodiments. To conducta coagulation test cycle, the disk is dropped from an initial or firstDisk Maximum Position, which may or may not be proximate the top of thetest chamber. As with prior embodiments, the first Disk Maximum positionis the highest point at which the disk is positioned during therespective test cycle. After releasing the force maintaining the disk atthe first Disk Maximum Position, the disk falls through the test fluidvia the force of gravity to a first Disk Minimum Position, which ismeasured (e.g., with a position detector) at the lowest point in whichthe disk settles. The disk is then dropped again from a second DiskMaximum Position after a specified period of time (either after liftingthe disk or from its current position as discussed in further detailbelow). After the disk settles, a second Disk Minimum Position ismeasured.

Lifting of the disk at the end of each test cycle can be specified bytest cycle duration time. The test cycle duration can be from about 0.5seconds to about 10 seconds, depending on the test needs. For example,if test cycle duration is 1 seconds, then a 999 second test is dividedup 999 test cycles. For each test cycle, a portion of time is used fordisk lift, and the remaining portion is for disk drop. For example, for1 second test cycle duration, 0.5 seconds can be used for disk lift andthe remaining 0.5 seconds can be used for disk drop. If the disk did notdrop to the bottom of the well from the previous test cycle, in the nexttest cycle, the disk can optionally start at the positon from the lasttest cycle. Therefore, the starting position can depend on test cycleduration and fluid sample viscosity. The starting position canpotentially be at the bottom, or somewhere in the middle of the well oreven at the top of the test chamber well. It can depend on how the assayis programmed. In some assay, the test duration and time distributionfor lift and drop are programmed so that the disk would start at theprevious Disk Minimum Position or bottom of the well at each test cycle(unless clot formed and disk is immobilized by the clot); in otherassay, the test duration and time distribution for lift and drop areprogrammed so that the disk would start from the top of the well or DiskMaximum Position at each test cycle.

A plurality of (e.g., three) preliminary test cycles are conducted toobtain a lowest Disk Minimum Position and a highest Disk MaximumPosition among the preliminary (e.g., first three) test cycles. Fromthis information, a Reference Disk-Span (i.e. the highest Disk MaximumPosition minus the lowest Disk Minimum Position) and a Reference DiskMinimum Position (i.e. the lowest measured Disk Minimum Position) areobtained. A Clot Detection Reference for the Disk Minimum Position iscomputed at step 714 by the following formula: the Clot DetectionReference (for Disk Minimum Position)=Reference Disk Minimum Position+(X%×Reference Disk-Span). X % is a pre-selected threshold coded between 0and 100% in assay protocol to adjust the Clot Detection Reference basedon Disk Minimum Position. The Reference Disk Minimum Position and theReference Disk-Span are updated in step 716 for the next test cycle if anew lowest in Disk Minimum Position or a new highest in Disk MaximumPosition are measured, and a new Clot Detection Reference is computedand updated. If no new lowest Disk Minimum Position or no new highestDisk Maximum Position is measured, the Reference Disk Minimum and theReference Disk-Span remain the same as at step 714, and the ClotDetection Reference is not changed from step 714. The Disk MinimumPosition of is compared at step 718 to the latest (most recent) ClotDetection Reference. At decision step 720, if the value of the DiskMinimum Position is greater than (>) the present Clot DetectionReference, clot detection is declared at 722. If the value of the DiskMinimum Position is less than (<) the present Clot Detection Reference,continue to update the reference Disk Minimum Position and the ReferenceDisk-Span for the next test cycle at step 716, and compute the mostrecent Clot Detection Reference, and evaluate the measurements obtainedfrom the new test cycle against the new or most recent Clot DetectionReference until clot detection is declared or the test otherwiseconcludes. To avoid false detection of a clot, the clot test continuesfor three or more test cycles (specified in assay protocol) when “>”condition is met at 720. If all of Disk Minimum Positions for threecontinuous test cycles meet the “>” Clot Detection Reference condition,clotting time is concluded from the first “>” test cycle. If the DiskMinimum Positions for three test cycles failed to meet the “>” ClotDetection Reference condition, then clot is not declared and testcontinues.

The pre-selected threshold X % used for calculating the Clot DetectionReference can vary, depending on the test period, as desired. In oneexample embodiment, the pre-selected threshold (X %) is not capable ofdetermining a clot for the first time period for seconds 0-250 (e.g., X% can be set at 40% or more) and the pre-selected threshold (X %) forthe second time period for seconds ˜250-450 is 10% and the pre-selectedthreshold (X %) the third time period for the remainder of thecoagulation test after 450 seconds is 8%.

As stated above and as illustrated in FIG. 19, the Disk Minimum Positioncan be only one of many parameters repeatedly measured 724 and updated716 for comparison to corresponding clot detection threshold pre-set byassay protocol for the respective time period 718. In this way, a clotcan be detected and the test can be concluded if any one of theplurality of parameters assessed (e.g., any or all of the first-fourthembodiments) exceeds the respective clot detection threshold. Clotdetection thresholds, references or the conditions at which a clot willbe detected for other assessed parameters can be assigned in mannersdiscussed above with respect to other embodiments.

Referring now also to a fifth embodiment 800, which is generallyoutlined in FIG. 20. In this embodiment, the measured Disk MinimumPosition values are also assessed, but in a different way. In thisembodiment, the initial setup and test cycles of steps 810-812 can beconducted as described with the fourth embodiment 710-712, and thelowest measured Disk Minimum Position is assigned as the Reference DiskMinimum Position 814 (as in the fourth embodiment at step 714) and theReference Disk-Span is calculated as the lowest Disk Maximum subtractedfrom the highest Disk Maximum (also as in the fourth embodiment at step714). However, to determine whether a change in Disk Minimum Position ina particular test cycle is significant enough to be considered as apotential clotting event, an Enabling Threshold (Y %) to startintegrating disk minimum position change is used to compute a Referencefor Enabling Integration of Disk Minimum Position Change at step 814using the following formula: Reference for Enabling Integration of DiskMinimum Position Change=Reference Disk Minimum Position+(Y %×ReferenceDisk-Span). The Reference Disk Minimum Position and/or the ReferenceDisk-Span are updated at step 816 if a new lowest Disk Minimum positionor a new highest Disk Maximum position is found or measured asadditional test cycles are conducted, and a new Reference for EnablingIntegration of Disk Minimum Position Change is computed. If no newlowest Disk Minimum Position or a new highest Disk Maximum Position arefound, the reference Disk Minimum Position and the Reference Disk-Spanremain the same as step 814, and the Reference for Enabling Integrationof Disk Minimum Position Change is not changed from step 814. TheEnabling Threshold (Y %) to start integrating changes in the DiskMinimum Position is used to eliminate any Change in Minimal Position(present Disk Minimum Position minus the lowest measured Disk MinimumPosition) caused by changes (i.e. noise) not associated to clotformation, such as possible sensor signal drift. Y % can be anywherebetween 0 to 100%. In one example, the Enabling Threshold preset byassay protocol is a 2% increase (or about 2%) in Reference Disk-Spanfrom the lowest measured Disk Minimum Position. The Disk MinimumPosition is compared to the latest Reference for Enabling Integration ofDisk Minimum Position Change at step 818. At decision point 820, if theChange in Minimal Position is below the Reference for EnablingIntegration of Disk Minimum Position Change calculated at step 814, aDisk Change Value is set at zero or the Change in Minimal Position isotherwise disregarded as not indicating a potential clotting event. Whenthe Change in Minimal Position is above the Reference for EnablingIntegration of Disk Minimum Position Change at step 820, then the DiskChange Value is computed at step 822 as the current Disk MinimumPosition subtracted from the most recent calculated Reference DiskMinimum Position. The current Disk Change Value for each cycle is addedto each of the previous Disk Change Values to calculate a DistanceMinimum Sum 822-824. The Distance Minimum Sum is compared with a ClotDetection Reference computed as Z %×Reference Disk-Span at step 826 andZ % is a Clot Detection Threshold pre-set by assay protocol for therespective time period. If the Distance Minimum Sum is above the ClotDetection Reference at step 828, a clot is detected 830. If the DistanceMinimum Sum is below the Clot Detection Reference at step 828, a clot isnot indicated to be detected and the test continues. If enabled for therespective time period, the Disk Change Value of the most current testcycle is added to the Disk Change Values (previous Distance Minimum Sum)of the subsequent test cycles to continually update the Distance MinimumSum until a clot is detected. In one example embodiment, the Change inMinimum Position or Distance Minimum Sum are not assessed or capable ofdetermining a clot for the first time period for seconds 0-250 and theClot Detection Threshold for the first time period for seconds ˜250-450is 40% of the lowest measured Disk Minimum Position and the ClotDetection Threshold for the third time period for the remainder of thecoagulation test is 25% of the lowest measured Disk Minimum Position.Therefore, the Clot Detection Threshold is variable based on both thetime period and the results of the test cycles conducted.

As indicated in FIG. 20 at steps 832 and 824-826, in some embodiments,the Distance Minimum Sum is assessed concurrently or otherwise incombination with one or more of the previously disclosedembodiments/parameters of the first through fourth embodiments in themanner as disclosed above. The one or more parameters can optionally beassessed dependent of the test period of the coagulation test phase. Forexample, in one illustrative embodiment, the test period is divided intothree test periods as in the fourth embodiment. The start time forenabling the modality of the fifth embodiment could be any time aftertest cycle started (after the Mix phase), but in some embodiments, thefifth embodiment is not enabled and is not assessed to evaluate clotformation until the coagulation test phase is in a test period in whichat least 250 seconds has elapsed (e.g., the second test period). In testperiod(s) including test cycles prior to 250 seconds and also duringtest period(s) after 250 seconds, the modalities of the first-fourthembodiments disclosed above can be optionally assessed in anycombination, as desired. A clot can be detected and the test can beconcluded if any one of the plurality of parameters assessed (e.g., anyor all of the first-fifth embodiments) exceeds the respective clotdetection threshold.

Example 2

FIG. 21 plots the results of an example of repeatedly monitoring changesin the disk Distance Span as a function of the elapsed time during aNG-HMS HR-ACT test as generally described above. The raw data used toplot FIG. 21 is provided in Table 2 provided below. In the presentexample, the target Activated Clotting Time was 514 seconds. It can beseen that noise 902 (generally referenced) due to factors other thanclot formation is present at the start of the test, prior to formationof an actual clot as generally referenced at 904. If the clot formationthreshold is set low, this noise 902 can surpass the low threshold,triggering a clot detection prematurely (i.e. false clot detection). Inthe present example, the clot detection threshold was set to a 20%reduction as compared to the previous test cycle for seconds 0-450seconds and a 10% reduction as compared to the previous test cycle fortest cycles occurring after 450 seconds. In assessing this modality, aclot was detected at 534.7 seconds.

Similarly, FIG. 22 plots the results of monitoring changes in the diskDrop Velocity as a function of test time during repeated test cycles asfurther discussed above. Once again, if the clot detection threshold isset low, noise 1002 (generally referenced) at the beginning of the testwould have triggered the clot detection premature to formation of anactual clot as generally referenced later in the test at 1004.Conversely, if the clot detection threshold is set to be higher as toexclude the noise, early detection of the forming clot would not beachieved. In the present example, the clot detection threshold was setto a 20% reduction as compared to the previous test cycle for seconds0-450 and a 10% reduction as compared to the previous test cycle forafter second 450. A clot was detected at 730.3 seconds. The raw dataused to plot FIG. 22 is also provided in Table 2 below.

As illustrated above, evaluating only changes disk Distance Span anddisk Drop Velocity can fail to detect the clot formation at an earlystage in the clot formation process. The present inventors have foundthat by evaluating changes in the Disk Minimum Position eitherindividually or in combination with one or more of the first-thirdembodiments, noise is smoothed out in the plotted test data so thatnoise does not trigger false detection of a clotting event while stillproviding early detection of a clot.

In support of this theory, the test results provided in Table 2 wereplotted to evaluate the measured Disk Minimal Position as a function oftest time in FIG. 23. In this embodiment, the coagulation test phase isbroken up into three test periods. One period being seconds 0-250, thesecond test period being between seconds 250-450 and the third testperiod being after second 450. The Clot Detection Threshold was set suchthat if the Disk Minimum Position is at least 10% increase from theinitial, first Disk Minimum Position during the second time period, clotdetection is triggered and in the third time period, a Disk MinimumPosition greater than 8% will trigger clot detection. Therefore, theDisk Minimum Position is not assessed or capable of triggering clotdetection in the first test period. In this example, the Disk MinimalPosition exceeds the 8% increase threshold for the second time period,at second 560.8, which triggers clot indication.

The graph of FIG. 24 shows how a clot is detected in the test of Table 2by assessing the Distance Minimum Sum as a function of time, whichincreases the sensitivity of the test as compared to the method of FIG.23. In this example, the Reference for Enabling Integration of DiskMinimum Position Change is set to be a 2% increase as compared thelowest measured Disk Distance Minimum. The Clot Detection Threshold isset such that if the Disk Change Value increases at least 40% ascompared to the lowest measured test cycle during seconds 0-450 (firsttime period), clot detection is triggered and after second 450 (secondtime period), an increase in the Disk Change Value greater than 25% ascompared to the lowest measure test cycle will trigger clot detection.In this example, Table 2 indicates that clot detection is triggered at521.7 seconds, which is also associated with a spike (signal) as seenplotted in the graph. Therefore, the modality of FIG. 24, of the fourmodalities of FIGS. 21-24, provided the earliest detection of the clotand also provided clot detection closest to the target ACT of 514seconds.

While the description above uses the procedures and values of clotdetection methods to describe certain details, the broadest scope of thedisclosure includes physical representations of that algorithm ormethods (such as an apparatus which relies on any combination of analogor digital hardware to implement the same), as well as methods ofcarrying out the algorithm and methods that do not depend upon thespecific physical components mentioned above but nonetheless achieve thesame or equivalent results. Therefore, the full scope of the presentdisclosure is described by the following claims.

COAGULATION TEST Fill Dist Dist Dist Dist Span Drop Vel Drop Dist MinDist Span Drop Vel Dist Min Dist Min Sum Clot Trig Dist Min Drop Sec MinMax Span ref ref Vel Sum Shows Clot* Shows Clot* Shows Clot* Shows Clot*meas Parameters ACT Sum Ratio Vel Ratio 0 DistSpan_Ref 0 0 8753 1939710644 11569    4 0 8763 19419 10656 DropVel_Ref 8 0 8753 19432 106799264   13 0 ActBySpan 17 0 534.7 21 1.2 8517 19457 10940 ActByVel 25 2.28488 19523 11035 730.3 29 3.3 8461 19483 11022 ActByDistMinSum 34 4.38302 19482 11180 521.7 38 5.4 8197 19468 11271 42 6.4 8160 19473 11313distMinSumRatio 46 7.4 8140 19477 11337   0.24 50 8.5 8117 19461 11344dropVelRatio 54 9.5 8124 19467 11343   0.91 58 10.6 8142 19462 11320Target ACT 64 11.6 8110 19478 11368 514   71 0 0.981326 12.6 8090 1944711357 Closest-Found ACT 74 0 0.999568 13.7 8078 19455 11377 509   78 01.00054 14.7 8108 19463 11355 82 0 1.000432 15.8 8090 19465 11375 85 01.00367 16.8 8130 19445 11315 88 0 1.004426 17.8 8155 19450 11295 92 00.952288 18.9 8077 19451 11374 96 0 0.998057 19.9 8114 19450 11336 99 00.746762 21 8087 19454 11367 102 0 0.729598 22 8094 19454 11360 106 01.006261 23.1 8073 19419 11346 110 0 0.996762 24.1 8099 19442 11343 1130 0.810557 25.1 8106 19429 11323 116 0 1.005829 26.2 8087 19443 11356120 0 1.009607 27.2 8046 19437 11391 124 0 1.007988 28.3 8183 1942011237 127 0 1.013493 29.3 8036 19439 11403 130 0 1.011766 30.3 806019431 11371 134 0 0.996978 31.4 8019 19435 11416 138 0 0.993955 32.48040 19429 11389 141 0 1.008528 33.5 8068 19437 11369 144 0 0.74622234.5 7985 19436 11451 148 0 0.969452 35.5 8098 19444 11346 152 01.009931 36.6 7971 19438 11467 155 0 0.963731 37.6 7995 19433 11438 1590 1.01101 38.7 8060 19434 11374 163 0 1.013925 39.7 8020 19432 11412 1670 0.972474 40.7 8032 19441 11409 172 0 1.006585 41.8 8056 19415 11359176 0 0.970207 42.8 7980 19421 11441 182 0 1.010255 43.9 7990 1942111431 187 0 1.010039 44.9 7986 19418 11432 192 0 0.951101 45.9 796319424 11461 198 0 1.001079 47 7991 19448 11457 204 0 1.008744 48 796519438 11473 210 0 0.972258 49.1 7960 19427 11467 217 0 1.00367 50.1 801619424 11408 224 0 1.005937 51.2 8206 19407 11201 231 0 0.967293 52.26937 19398 12461 238 0 0.945272 53.2 7938 19416 11478 246 0 0.9606 54.37952 19416 11464 255 0 1.000972 55.3 7907 19415 11508 264 0 0.99978456.4 7946 19421 11475 273 0 0.961896 57.4 7956 19417 11461 283 00.994711 58.4 7972 19380 11408 293 0 0.997841 59.5 8034 19404 11370 3040 0.984564 60.5 8019 19389 11370 315 0 0.957686 60.5 327 0 0.982837 648032 19496 11464 339 0 0.990069 64 352 0 0.981326 67.5 7973 19503 11530365 0 0.996978 67.5 378 0 0.987263 71 8088 19490 11402 391 0 0.979814 7111530 9264 404 0 0.980138 71 9091 0 0 0 0 0 NULL 417 0 0.974093 71 430 00.968912 74.5 8024 19478 11454 443 0.021263722 0.944193 74.5 11530 9264456 0.043564699 0.956498 74.5 9260 0 0 0 0 0 NULL 470 0.0712248250.946244 74.5 482 0.107010113 0.921308 78 7971 19497 11526 4960.165269254 0.89918 78 11532 9264 509 0.244446365 0.909003 78 9269 0 0 00 0 NULL 522 0.342207624 0.872085 78 535 0.452243063 0.871546 81.5 798419493 11509 548 0.570057913 0.826209 81.5 11532 9264 561 0.7054196560.854814 81.5 9268 0 0 0 0 0 NULL 574 0.839830582 0.808398 81.5 5870.976661769 0.817789 85 7999 19483 11484 600 1.118765667 0.787133 859298 0 0 0 0 0 NULL 613 1.262684761 0.784111 85 626 1.406430979 0.75237588.5 7994 19471 11477 639 1.553894027 0.724849 88.5 9305 0 0 0 0 0 NULL652 1.704814591 0.675734 88.5 665 1.855302965 0.615609 92 7992 1945011458 678 2.008384476 0.511766 92 8822 0 0 0 0 0 NULL 691 2.1665658220.413212 92 704 2.34851759 0.298359 95.5 7960 19483 11523 7172.633330452 0.211464 95.5 11543 9264 730 3.057394762 0.14864 95.5 9246 00 0 0 0 NULL 743 3.663670153 0.087435 95.5 756 4.321808281 0.074806 997963 15688 7725 770 5.026795747 0.065091 99 6918 0 0 0 0 0 NULL 7820.121963869 0.04987 99 796 0.867058518 0.048467 102.5 7977 15630 7653809 1.630045812 0.047064 102.5 6759 0 0 0 0 0 NULL 822 2.4089376780.042854 102.5 835 3.193015818 0.03886 106 7971 19491 11520 106 9322 0 00 0 0 NULL 106 109.5 7983 19475 11492 109.5 9234 0 0 0 0 0 NULL 109.5113 7946 16263 8317 113 11543 9264 113 7509 0 0 0 0 0 NULL 113 116.57959 19506 11547 116.5 11547 9264 116.5 9318 0 0 0 0 0 NULL 116.5 1207937 19478 11541 120 11569 9264 120 9353 0 0 0 0 0 NULL 120 123.5 795119491 11540 123.5 11569 9264 123.5 9338 0 0 0 0 0 NULL 123.5 127 795119497 11546 127 11569 9264 127 9389 0 0 0 0 0 NULL 127 130.5 7971 1948411513 130.5 9373 0 0 0 0 0 NULL 130.5 134 7995 19486 11491 134 9236 0 00 0 0 NULL 134 137.5 7993 19454 11461 137.5 9208 0 0 0 0 0 NULL 137.5141 7943 19445 11502 141 9343 0 0 0 0 0 NULL 141 144.5 7894 15662 7768144.5 11569 9264 144.5 6913 0 0 0 0 0 NULL 144.5 148 7978 19451 11473148 8981 0 0 0 0 0 NULL 148 151.5 7962 19453 11491 151.5 9356 0 0 0 0 0NULL 151.5 155.2 7988 19452 11464 155.2 8928 0 0 0 0 0 NULL 155.2 159.17967 19468 11501 159.1 9366 0 0 0 0 0 NULL 159.1 163.1 7936 19465 11529163.1 9393 0 0 0 0 0 NULL 163.1 167.4 7978 19447 11469 167.4 9009 0 0 00 0 NULL 167.4 171.8 7948 19468 11520 171.8 9325 0 0 0 0 0 NULL 171.8176.5 7976 19442 11466 176.5 8988 0 0 0 0 0 NULL 176.5 181.5 7956 1947611520 181.5 9359 0 0 0 0 0 NULL 181.5 186.6 7957 19465 11508 186.6 93570 0 0 0 0 NULL 186.6 192 8005 19458 11453 192 8811 0 0 0 0 0 NULL 192197.7 7966 19457 11491 197.7 9274 0 0 0 0 0 NULL 197.7 203.7 7998 1945211454 203.7 9345 0 0 0 0 0 NULL 203.7 210 7953 19445 11492 210 9007 0 00 0 0 NULL 210 216.6 7961 19454 11493 216.6 9298 0 0 0 0 0 NULL 216.6223.5 7935 19466 11531 223.5 9319 0 0 0 0 0 NULL 223.5 230.8 7965 1944511480 230.8 8961 0 0 0 0 0 NULL 230.8 238.4 7957 19447 11490 238.4 87570 0 0 0 0 NULL 238.4 246.4 7969 19458 11489 246.4 8899 0 0 0 0 0 NULL246.4 254.8 7953 19468 11515 254.8 9273 0 0 0 0 0 NULL 254.8 263.7 804619464 11418 263.7 9262 0 0 0 0 0 NULL 263.7 272.9 7972 19450 11478 272.911569 9264 272.9 8911 0 0 0 0 0 NULL 272.9 282.7 7998 19444 11446 282.79215 0 0 0 0 0 NULL 282.7 292.9 7968 19443 11475 292.9 9244 0 0 0 0 0NULL 292.9 303.6 8037 19459 11422 303.6 9121 0 0 0 0 0 NULL 303.6 314.98040 19447 11407 314.9 8872 0 0 0 0 0 NULL 314.9 326.7 8035 19464 11429326.7 9105 0 0 0 0 0 NULL 326.7 339.1 8039 19456 11417 339.1 9172 0 0 00 0 NULL 339.1 352.2 8036 19457 11421 352.2 9091 0 0 0 0 0 NULL 352.2365.2 8019 19456 11437 365.2 9236 0 0 0 0 0 NULL 365.2 378.2 8034 1946711433 378.2 9146 0 0 0 0 0 NULL 378.2 391.3 8028 19470 11442 391.3 90770 0 0 0 0 NULL 391.3 404.3 7968 19468 11500 404.3 9080 0 0 0 0 0 NULL404.3 417.4 8032 19458 11426 417.4 9024 0 0 0 0 0 NULL 417.4 430.4 803119460 11429 430.4 8976 0 0 0 0 0 NULL 430.4 443.4 8140 19467 11327 443.48747 246 0 0 0 0 NULL 443.4 456.5 8152 19471 11319 456.5 8861 504 0 0 00 NULL 456.5 469.5 8214 19473 11259 469.5 8766 824 0 0 0 0 NULL 469.5482.5 8308 19458 11150 482.5 11569 9264 482.5 8535 1238 0 0 0 0 NULL482.5 495.6 8568 19463 10895 495.6 8330 1912 0 0 0 0 NULL 495.6 508.68810 19477 10667 508.6 8421 2828 0 0 0 0 NULL 508.6 521.7 9025 1945010425 521.7 8079 3959 0 0 0 1 NULL 521.7 534.7 9167 19449 10282 534.78074 5232 1 0 0 2 NULL 534.7 547.7 9257 19449 10192 547.7 7654 6595 2 00 3 DIST_MIN_SUM 547.8 547.8 547.8 547.8 560.8 9460 19476 10016 560.87919 8161 3 0 0 4 DIST_SPAN 560.8 573.8 9449 19455 10006 573.8 7489 97164 0 0 5 DIST_SPAN 573.8 586.9 9477 19493 10016 586.9 7576 11299 5 0 0 6DIST_SPAN 586.9 599.9 9538 19461 9923 599.9 7292 12943 6 0 0 7 DIST_SPAN599.9 613 9559 19499 9940 613 7264 14608 7 0 0 8 DIST_SPAN 613 626 955719508 9951 626 6970 16271 8 0 0 9 DIST_SPAN 626 639 9600 19490 9890 6396715 17977 9 0 0 10 DIST_SPAN 639 652.1 9640 19503 9863 652.1 6260 1972310 0 0 11 DIST_SPAN 652.1 665.1 9635 19509 9874 665.1 5703 21464 11 0 012 DIST_SPAN 665.1 678.2 9665 19479 9814 678.2 4741 23235 12 0 0 13DIST_SPAN 678.2 691.2 9724 19493 9769 691.2 3828 25065 13 0 0 14DIST_SPAN 691.2 704.2 9999 19498 9499 704.2 2764 27170 14 0 0 15DIST_SPAN 704.2 717.3 11189 19495 8306 717.3 1959 30465 15 0 0 16DIST_SPAN 717.3 730.3 12800 19476 6676 730.3 1377 35371 16 1 0 17DIST_SPAN 730.3 743.4 14908 19470 4562 743.4 810 42385 17 2 0 18DIST_SPAN 743.4 756.4 15508 19480 3972 756.4 693 49999 18 3 0 19DIST_SPAN 756.4 769.5 16050 19444 3394 769.5 603 58155 19 4 0 20DIST_SPAN 769.5 782.5 16686 19448 2762 782.5 462 1411 20 5 0 0 DIST_SPAN782.5 795.5 16514 19440 2926 795.5 449 10031 21 6 0 1 DIST_SPAN 795.5808.6 16721 19456 2735 808.6 436 18858 22 7 0 2 DIST_SPAN 808.6 821.616905 19462 2557 821.6 397 27869 23 8 0 3 DIST_SPAN 821.6 834.7 1696519445 2480 834.7 360 36940 24 9 0 4 DIST_SPAN 834.7

What is claimed is:
 1. A method of detecting the formation of a clot ina fluid sample during a coagulation test phase including one or moretest periods, the method comprising: a. providing a test chamber havinga top and a bottom and further providing a disk positioned within thetest chamber; b. filling the test chamber with the fluid sample; c.conducting a plurality of test cycles, each test cycle including: i.positioning the disk at a disk maximum position within the test chamber;wherein the disk maximum position is the highest point at which the diskis positioned during the respective test cycle; ii. dropping the disk;iii. determining a highest disk maximum position which is the highestdisk maximum position measured during all of the test cycles conducted;and iv. determining a current disk minimal position which is the lowestposition at which the disk falls within the test chamber during the lasttest cycle and a lowest disk minimal position which is the lowest diskminimal position measured during all of the test cycles conducted; d.calculating a reference disk-span being equal to the highest diskmaximum position minus the lowest disk minimum position; e. identifyinga reference for enabling disk minimum position being equal to the lowestdisk minimal position; f. calculating a reference for enablingintegration of disk minimum position equaling the reference disk minimumposition+(Y %×the reference disk-span); wherein Y % is a value between 0and 100%; g. subtracting the lowest disk minimal position from thecurrent disk minimal position to calculate a change in minimal position;h. comparing the change in minimal position to the reference forenabling integration of disk minimum position; wherein, if the change inminimal position is less than the reference for enabling integration ofdisk minimum position, a clot will not be indicated to be detected andwhen the change in minimal position is greater than the reference forenabling integration of disk minimum position, then a disk change valueis set to be the change in minimal position; i. adding each disk changevalue of all conducted test cycles to calculate a distance minimum sum;and j. during at least one specified test period, comparing the distanceminimum sum to a clot detection reference; wherein if the distanceminimum sum is greater than the clot detection reference, a clot isindicated to be detected; wherein if the distance minimum sum is notgreater than the clot detection reference, a clot is not indicated to bedetected.
 2. The method of claim 1, further comprising the step ofmeasuring a first parameter during each test cycle; wherein the firstparameter is indicative of a viscosity of the fluid sample.
 3. Themethod of claim 2, further comprising the step of assessing the firstparameter either indicating a clot to be detected or not indicating aclot to be detected independent of step (j).
 4. The method of claim 3,further comprising the step of measuring a second parameter during eachtest cycle; wherein the second parameter is indicative of a viscosity ofthe fluid sample.
 5. The method of claim 4, further comprising the stepof assessing the second parameter and the first parameter and eitherindicating a clot to be detected or not indicating a clot to be detectedindependent of step (j).
 6. The method of claim 1, wherein each testcycle is conducted in an equal amount of time.
 7. The method of claim 1,wherein the disk is made of a ferromagnetic material.
 8. The method ofclaim 1, wherein a height of the test chamber is divided into aplurality of lift zones; wherein during step (c)(i) the disk ispositioned with a magnetic field and the magnetic field varies dependingon the lift zone in which the disk originates.
 9. The method of claim 1,wherein the clot detection reference varies as the repeated test cyclesare conducted.
 10. The method of claim 1, wherein the fluid sampleincludes heparin.
 11. The method of claim 1, wherein the fluid sampleincludes a viscosity-altering substance and the method furthercomprising a sample mix phase prior to step (c).
 12. The method of claim1, wherein the clot detection reference is set to equal a clot detectionthreshold×the Reference Disk-Span.
 13. The method of claim 12, whereinthe clot detection threshold changes over time.
 14. The method of claim1, wherein Y % is about 2%.
 15. A method of detecting the formation of aclot in a fluid sample during a coagulation test phase including one ormore test periods, the method comprising: a. providing a test chamberhaving a top and a bottom and further providing a disk positioned withinthe test chamber; b. filling the test chamber with the fluid sample; c.conducting a first test cycle including: i. positioning the disk at afirst disk maximum position within the test chamber; wherein the firstdisk maximum position is the highest point at which the disk ispositioned during the first test cycle; ii. measuring the first diskmaximum position; iii. dropping the disk; and iv. determining a firstdisk minimal position which is the lowest point at which the disk fallswithin the test chamber during the first test cycle; d. conducting asecond test cycle including: v. positioning the disk at a second diskmaximum position within the test chamber; wherein the second diskmaximum position is the highest point at which the disk is positionedduring the second test cycle; vi. measuring the second disk maximumposition; vii. dropping the disk; and viii. determining a second diskminimal position which is the lowest point at which the disk fallswithin the test chamber during the second test cycle; e. conducting athird test cycle including: ix. positioning the disk at a third diskmaximum position within the test chamber; wherein the third disk maximumposition is the highest point at which the disk is positioned during thethird test cycle; x. measuring the third disk maximum position; xi.dropping the disk; and xii. determining a third disk minimal positionwhich is the lowest point at which the disk falls within the testchamber during the third test cycle; k. calculating a referencedisk-span being equal to the highest of the first-third disk maximumpositions minus the lowest of the first-third disk minimum positions; l.identifying a reference disk minimum position being equal to the lowestof the first-third disk minimum positions; m. calculating a clotdetection reference being equal to the reference disk minimumposition+(X %×the Reference Disk Span); wherein X % is a value between 0and 100%; f. conducting a fourth test cycle including: i. positioningthe disk at a fourth disk maximum position within the test chamber;wherein the fourth disk maximum position is the highest point at whichthe disk is positioned during the fourth test cycle; ii. measuring thefourth disk maximum position; iii. dropping the disk; and iv.determining a fourth disk minimal position which is the lowest point atwhich the disk falls within the test chamber during the fourth testcycle; and g. comparing the fourth disk minimum position to the clotdetection reference; and h. repeating steps f(i-iv) to conduct fifth andsixth test cycles and comparing the fifth and sixth disk minimumpositions to the clot detection reference; and i. either declaring aclot to be detected when all of the fourth-sixth disk minimum positionsare greater than the clot detection reference or not indicating a clotto be detected when any of the fourth-sixth disk minimum positions arenot greater than the clot detection reference.
 16. The method of claim15, further comprising the step of measuring a first parameter duringstep (f)(ii); wherein the first parameter is indicative of a viscosityof the fluid sample.
 17. The method of claim 16, further comprising thestep of assessing a change in the first parameter and either indicatinga clot to be detected or not indicating a clot to be detectedindependent of step (i).
 18. The method of claim 15, wherein, after step(g), the method further comprises the steps of updating each of: 1) thereference disk-span being equal to the highest of the first-fourth diskmaximum positions minus the lowest of the first-fourth disk minimumpositions; 2) the reference disk minimum position to equal the lowest ofthe first-fourth disk minimum positions; and 3) the clot detectionreference.
 19. The method of claim 15, wherein X % is greater than about8%.
 20. The method of claim 15, wherein X % varies throughout thecoagulation test phase.